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Background  Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting  TCF20  function in patients with ID, ASD, and hypotonia have been reported.  TCF20  encodes a transcriptional co-regulator structurally related to  RAI1 , the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity).    Methods  Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in  TCF20 . We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.    Results  We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of  TCF20 . The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.    Conclusions   TCF20  pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of  TCF20 -associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.    Electronic supplementary material  The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

genome medicine

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome